Medulloblastoma (MB) is the most common malignant brain tumor diagnosed in children. The poor prognosis of children with MB in terms of long-term sequelae challenges us to investigate new treatment modalities. Tumor growth and angiogenesis occur in the context of the extracellular matrix (ECM), the levels and deposition of which are controlled in part by secreted protein, acidic and rich in cysteine (SPARC), a matricellular glycoprotein. SPARC modulates cellular interaction with the ECM and has diverse roles in normal cells, many of which have been shown to contribute to tumorigenesis. The relative levels of SPARC expression in normal brain decreased with malignant transformation, as indicated by its decrease in immunohistochemical staining for SPARC in medulloblastoma tumor samples. Our preliminary data show that medulloblastoma cells stably overexpressing SPARC exhibit reduced proliferation, adhesion, angiogenesis and tumor growth. We hypothesize that SPARC is deregulated in medulloblastoma. The present proposal will investigate the precise biological and molecular mechanisms by which SPARC expression might contribute to improved tumor therapy. Specific aim 1 will evaluate the underlying mechanisms involved in the anti-proliferative and anti-adhesive functions of SPARC in medulloblastoma cell lines. Specific aim 2 will investigate whether SPARC expression can suppress pre-formed tumor growth and angiogenesis in nude mice using an orthotopic human medulloblastoma model. We will also identify the signaling networks that are altered by SPARC expression to better characterize its role in the regulation of distinct cellular aspects of medulloblastoma tumor angiogenesis. Specific aim 3 will investigate the potential synergistic effects between SPARC expression and irradiation in medulloblastoma cells. We will first determine whether overexpression of SPARC results in radiosensitivity and possible mechanisms in vitro. We will also determine the biological significance of combining SPARC with radiotherapy using an orthotopic medulloblastoma model. This preclinical investigation will provide the biological basis for potential SPARC-based gene therapy, which could be utilized with current therapeutic modalities to affect tumor regression in patients with medulloblastoma. PUBLIC HEALTH RELEVANCE: Medulloblastoma is the most common malignant brain tumor in children. Postoperative radiation of the whole central nervous system (CNS) is one of the major treatment methods. However, an increasing number of long-term survivors with secondary effects from this treatment highlighted the need for development of novel therapeutic approaches. This proposal represents a comprehensive analysis to determine therapeutic benefit of SPARC expression for the treatment of medulloblastoma.